APPLICATION NOTE 42162
CHN determination in Fluorine-Compounds
with the Thermo Scientific FlashSmart
Elemental Analyzer
Authors
Introduction
Dr. Liliana Krotz, and
Dr. Guido Giazzi,
Thermo Fisher Scientific,
Milan, Italy
Fluoro-organic compounds exhibit unique properties and their potential is
increasingly being exploited in various areas of life sciences, particularly in
pharmaceutical and crop-protection fields.
Keywords
CHN, Fluorine Compounds,
IQ/OQ, Organic Synthesis,
Pharmaceuticals
Goal
This application note shows the
accuracy and robustness of the
Thermo Scientific FlashSmart EA
used for fluorine applications.
For example, many of the fluoro-compounds, the fluorosilicate (SiF6)-2, are
used in industrial solutions such as insecticides and antiseptics, and at
low concentrations are used in toothpaste and mouthwash preparation.
Applications have also been found using Teflon® (PTFE–polytetrafluoroethilene),
a fluoro-polymer which is very resistant to acid attack and is used in the car
industry and in the production of special vessels such as non-stick looking
utensils. Furthermore, some per-fluorate hydrocarbons are used as very
stable lubricant oils.
However, in the last fifteen years fluorine-containing drugs have become an
important tool in medicinal chemistry, as shown by its widespread use in the
drugs currently available on the market. Many fluorine compounds have been
developed and tested to enhance metabolic stability, which influences acidity
and basicity levels in the human body.
This application note was developed with the great
support of Dr Keiko Bando of DaiNippon, Osaka,
Japan, who has supplied us with many of the samples
evaluated, and supported us with her wide experience in
fluorine-compounds analysis.
Fluorine compounds in OEA analysis
Fluorine is very reactive. It reacts with catalysts, the tin
container and with the silica present in the quartz reactor.
Consequently, it affects the robustness of the analytical
system and the resistance time is proportional to the
fluorine concentration in the molecule.
Method
The FlashSmart Elemental Analyzer is based on the
dynamic combustion of the sample. The materials to be
analyzed are weighed in tin containers and introduced
into the combustion reactor via the Thermo Scientific™
MAS Plus Autosampler with oxygen. After combustion
of the sample, the gases produced are carried by a
helium flow to the combustion reactor filled with the
FluoAdso, then through the oxidation reduction catalysts,
a GC column. They are finally detected by a Thermal
Conductivity Detector (TCD).
Figure 1. Thermo Scientific FlashSmart Elemental Analyzer.
Figure 2. CHN configuration for Fluorine-Containing Compounds.
The fluorine compounds, which were analyzed for this
application have a concentration range from 3% to 55%.
Although fluorine reaction affects the analytical system,
the Thermo Scientific™ FlashSmart™ Elemental Analyzer
provides a solution to overcome this challenge.
A complete CHN report is automatically generated by the
Thermo Scientific™ EagerSmart™ Data Handling Software
and displayed at the end of the analysis.
A short layer of FluoAdso, constituting a mixture of
different oxides, was placed in the hot area of the
oxidation reactor where the flash combustion occurs.
The adsorber reacts with the fluorine-compounds, saving
catalysts and the quartz reactor wall.
Analytical Conditions
Oxidation/Reduction Furnace
950 °C
GC Column Oven
75 °C
Helium Carrier Flow
140 ml/min
Helium Reference Flow
100 ml/min
Oxygen Flow
250 ml/min
Oxygen Injection Time
5 sec
Sample Delay Time
12 sec
Total Run Time
less than 8 min
Standard
Acetanilide
Standard Weight
0.8-1.2 mg
Sample Weight
0.8-1.2 mg
Calibration Method
K factor
NH 2
F
H 3C
F
COOH
O
COOCH2CH3
F
N
N
HN
O
N
F
F
F
H 3C
NACC 001
NACC 002
NH2
F
O
Table 2. Accuracy of CHN determination.
COOH
N
F
Sample
F
F
Table 2, 3 and 4 show the comparison of theoretical
and experimental values of different fluorine
containing compounds analyzed 5 times, in which the
concentrations of fluorine is from 2 to 60%. The data
obtained demonstrates the repeatability capabilities of the
system for this matrix. No memory effect was observed,
meaning that there were no interference of the fluorine.
F
NACC 001*
NACC 003
CH3
F
O
NACC 002
F
COOH
N
F
NACC 003
F
F
COOH
F
F
F
COOH
F
NACC 004
NACC 004
NACC 005
F
F
F
CN
NACC 005
NH2
CN
F
CN
F
F
F
NACC 008
CN
NACC 008
NACC 011
NACC 011
Results
F
N
C
H
F
N
C
H
F
N
C
H
F
N
C
H
F
N
C
H
F
N
C
H
F
N
C
H
9.68
14.28
58.16
5.65
23.08
4.25
54.72
3.37
25.66
7.57
51.91
1.91
25.73
3.79
55.3
2.18
31.92
0
40.36
0.85
37.98
14.00
48.02
0
28.91
21.31
48.75
1.02
* The NACC 001 sample is an antibiotic traded as Spara®.
To validate the system, organic compounds with different
concentrations of fluorine were chosen. Instrument
calibration was performed with acetanilide using K factor
as calibration method.
Table 1 shows the theoretical and experimental data of
a Reference Material, BRC 73, analyzed in three series
of a large number of runs to evaluate the reproducibility,
accuracy and precision.
Table 1. CHN determination of BCR 73 Reference Material.
Theoretical Data
N%
C%
H%
8.89
50.81
3.84
Experimental Data
N%
RSD%
C%
RSD%
H%
RSD%
1
N. of
runs
40
8.78
0.34
50.81
0.38
3.84
1.21
2
15
8.81
0.42
50.84
0.38
3.82
0.80
3
35
8.83
0.40
50.96
0.03
3.87
0.89
Series
Calculated %
BCR 73: 1-[1-(-4bromophenylmethyl)-4-piperidinyl] - 5-chloro-2
(trifluoromethyl)-1H-benzimidazole
Experimental Data
%
RSD%
14.28
58.35
5.68
0.283
0.179
0.269
4.24
54.90
3.34
0.136
0.038
0.173
7.40
52.18
1.97
0.135
0.067
0.155
3.77
55.44
2.10
0.153
0.101
0.262
0.00
40.59
0.84
0.000
0.384
0.690
13.95
47.88
0.00
0.504
0.588
0.000
21.01
48.99
0.98
0.595
0.470
0.591
Table 3. Accuracy of CH Determination.
F
F
F
F
F
F
F
CO
F
F
NACC 012
RSD%
NACC 007
39.28
0.52
0.291
0.794
NACC 009
N%
C%
H%
F%
43.32
1.04
39.16
43.37
1.03
0.237
0.813
NACC 010
N%
C%
H%
F%
43.32
1.04
39.16
43.51
1.01
0.216
0.351
NACC 012
N%
C%
H%
F%
43.14
56.86
43.08
-
0.039
-
NACC 013
N%
C%
H%
F%
43.12
52.46
43.21
-
0.264
-
F
F
F
F
F
F F
%
NACC 010
F
F F
F
F
F
NACC 013
Experimental Data
39.64
0.48
44.79
F
NACC 009
Calculated %
N%
C%
H%
F%
F
F
F
NACC 007
F
Sample
F
F
F
COOH
F
COOH
F
COOH
F
Table 4: Accuracy of CHN determination.
CONHCH2
CI
CH 2COOH
O
N
OC2H 5
H2N
H 2N
F 2 H2O
CONHCH2
CI
NACC 016
F
OC2H 5
Sample
O
CI
OC2H5
CH2
CONHCH2
(COOH) 2
O
H2N
OC 2H5
Experimental Data
%
RSD%
NACC 014*
6.46
49.89
5.74
29.54
5.45
2.92
6.44
50.11
5.73
-
0.090
0.192
0.201
-
NACC 015
N%
C%
H%
Cl%
F%
9.96
59.78
5.97
8.40
4.51
9.89
59.92
5.98
-
0.210
0.059
0.096
-
NACC 016
N%
C%
H%
O%
Cl%
F%
7.69
50.56
4.80
20.49
12.98
3.48
7.62
50.68
4.78
-
0.200
0.199
0.526
-
NACC 017
N%
C%
H%
O%
F%
9.59
57.54
5.75
16.18
10.95
9.52
57.71
5.78
-
0.182
0.108
0.173
-
N
F
Calculated %
N%
C%
H%
O%
Cl%
F%
CH2
NACC 015
N
H 2N
CONHCH2
N
CH 2COOH
CH2
NACC 014
CI
CI
HO CCOOH
O
CH2
CI
NACC 017
* The NACC 014 is a gastro movement acceleration pharmaceutical present in the market with
Gasmotin® trade name.
Conclusion
Among halogens, only fluorine concentrations affects
CHN determination as it causes tailing or splitting of the
hydrogen peak. The use of a special FluoAdso, placed
in the hot part of the combustion reactor eliminates the
high activity of the fluorine compounds and it allows
the quantitative determination of CHN with excellent
accuracy and precision.
The lifetime of the reactor, when analyzing fluorine
compounds, is 150 – 200 samples, depending on the
sample nature and the fluorine concentration in the
chemical compounds. The use of the adsorber in CHN
configuration completely eliminates any interference of
fluorine and other halogens atoms, chlorine, bromine
and iodine do not influence CHN determination and no
dedicated hanlding measures need to be taken.
Acknowledgments
Dr Keiko Bando, Nichiei Sangyo Co.,Ltd, Dainippon
Pharmaceutical, Osaka, Japan
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